Old dogs, new tricks

Abstract

Many hyperalgesic states and the development of tolerance to morphine converge at the cellular level through the activation of the N-methyl-D-aspartic acid (NMDA) receptor and common signal transduction events including the activation of protein kinase C. Some commonly used opioids and their derivatives possess NMDA receptor antagonist activity. In preclinical models, the behavioral consequences of this activity, as illustrated by the dextro isomer of methadone, are antihyperalgesic effects and the attenuation of morphine tolerance. These observations suggest that the combination of an opioid plus NMDA receptor antagonist activity should be of particular value in pain states where the potency of the opioid has been reduced as a result of hyperalgesia and/or opioid tolerance. One strategy for the development of these observations includes evaluation of these established opioids and their derivatives in clinical studies directed at improving the therapeutic window of the opioid.